Method of Treating Cancer and Bone Cancer Pain

ABSTRACT

This invention is directed to the treatment of cancer, particularly lung cancer, breast cancer, melanoma, renal cell carcinoma, thyroid cancer that has metastasized to the bone. The invention is also directed to a method for treating bone cancer pain in an individual in need of such treatment comprising administering to the individual an effective amount of a compound of Formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalApplication No. 61/481,682, filed May 2, 2011, and U.S. ProvisionalApplication No. 61/557,366, filed Nov. 8, 2011, all of which areincorporated herein by reference.

FIELD OF THE INVENTION

This invention is directed to the treatment of cancer, particularly tocancers where bone disease is common. These cancers include breastcancer, melanoma, renal cell carcinoma, and thyroid cancer, as well asothers, using a compound of Formula I as disclosed herein. In additionto treating these forms of cancer, the compound of Formula I can be usedto treat the pain associated with bone metastases. The ability of thecompound of Formula I to treat these and other forms of cancer and theassociated bone pain can be monitored using imaging technologies,including magnetic resonance imaging, among other methods.

BACKGROUND OF THE INVENTION

Bone disease is common in patients with prostate cancer, lung cancer,breast cancer, melanoma, renal cell carcinoma, and thyroid cancer. As anexample, Castration-Resistant Prostate Cancer (CRPC) is a leading causeof cancer-related death in men. Despite progress in systemic therapy forCRPC, improvements in survival are modest, and virtually all patientssuccumb to this disease with a median survival of about 2 years. Theprimary cause of morbidity and mortality in CRPC is metastasis to thebone, which occurs in about 90% of cases.

Metastasis to bone is a complex process involving interactions betweenthe cancer cell and components of the bone microenvironment includingosteoblasts, osteoclasts, and endothelial cells. Bone metastases causelocal disruption of normal bone remodeling, and lesions generally show apropensity for either osteoblastic (bone-forming) or osteolytic(bone-resorbing) activity. Although most CRPC patients with bonemetastases display features of both types of lesions, prostate cancerbone metastases are often osteoblastic, with abnormal deposition ofunstructured bone accompanied by increased skeletal fractures, spinalcord compression, and severe bone pain.

The receptor tyrosine kinase MET plays important roles in cell motility,proliferation, and survival, and has been shown to be a key factor intumor angiogenesis, invasiveness, and metastasis. Prominent expressionof MET has been observed in primary and metastatic prostate carcinomas,with evidence for higher levels of expression in bone metastasescompared to lymph node metastases or primary tumors.

MET signaling can influence osteoblast and osteoclast function. Strongimmunohistochemical staining of MET has been observed in osteoblasts indeveloping bone, while both HGF and MET are expressed by osteoblasts andosteoclasts in vitro and regulate cellular responses such asproliferation, migration and differentiation. Secretion of HGF byosteoblasts has been proposed as a key factor in osteoblast/osteoclastcoupling and is thought to promote the development of bone metastases bytumor cells that express MET.

Vascular endothelial growth factor (VEGF) and its receptors onendothelial cells are widely accepted as key mediators in the process oftumor angiogenesis. In prostate cancer, elevated VEGF in either plasmaor urine is associated with shorter overall survival. VEGF may also playa role in activating the MET pathway in tumor cells by binding toneuropilin-1, which is frequently upregulated in prostate cancer andappears to activate MET in a co-receptor complex. Agents targeting theVEGF signaling pathway have demonstrated some activity in patients withCRPC, as well as breast cancer, melanoma, renal cell carcinoma, andthyroid cancer.

Like MET, the VEGF signaling pathway is strongly implicated in boneformation and remodeling. Both osteoblasts and osteoclasts express VEGFand VEGF receptors, which appear to be involved in autocrine and/orparacrine feedback mechanisms regulating cell proliferation, migration,differentiation and survival [62-66]. Experiments using geneticallymodified mice have shown that angiogenesis and VEGF signaling inosteoblasts are both important in bone development and repair.

A need remains for methods of treating cancer in human patients withbreast cancer, melanoma, renal cell carcinoma, and thyroid cancer, andthe bone metastases associated with these forms of cancer. A need alsoremains for a method of treating bone cancer or pain associated withbone metastases in individuals in need of such treatment.

SUMMARY OF THE INVENTION

These and other needs are met by the present invention which is directedto a method for treating bone cancer associated with breast cancer,melanoma, renal cell carcinoma, lung cancer, and thyroid cancer. Themethod comprises administering a therapeutically effective amount of acompound that modulates both MET and VEGF signaling to a patient in needof such treatment. In some embodiments, the bone cancer is bonemetastases associated with breast cancer, melanoma, renal cellcarcinoma, and thyroid cancer.

In one aspect, the present invention is directed to a method fortreating bone metastases, lung cancer, breast cancer, melanoma, renalcell carcinoma, or thyroid cancer, or bone metastases associated withbreast cancer, melanoma, renal cell carcinoma, or thyroid cancer,comprising administering a therapeutically effective amount of acompound that modulates both MET and VEGF signaling to a patient in needof such treatment. In some embodiments, the bone cancer or metastases isosteoblastic bone cancer or bone metastases.

In one embodiment of this and other aspects, the dual acting MET/VEGFinhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is halo;

R² is halo;

R³ is (C₁-C₆)alkyl;

R⁴ is (C₁-C₆)alkyl; and

Q is CH or N.

In another embodiment, the compound of Formula I is compound 1:

or a pharmaceutically acceptable salt thereof. Compound 1 is known asN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

In another aspect, the invention provides a method for treating bonemetastases associated with lung cancer, breast cancer, melanoma, renalcell carcinoma, or thyroid cancer, comprising administering atherapeutically effective amount of a pharmaceutical formulation to apatient in need of such treatment comprising Compound of Formula I orthe malate salt of Compound of Formula I or another pharmaceuticallyacceptable salt of Compound of Formula I, to a patient in need of suchtreatment.

In another aspect, the invention provides a method for reducing orstabilizing metastatic bone lesions associated with lung cancer, breastcancer, melanoma, renal cell carcinoma, or thyroid cancer, comprisingadministering a therapeutically effective amount of a pharmaceuticalformulation to a patient in need of such treatment comprising Compoundof Formula I or the malate salt of Compound of Formula I or anotherpharmaceutically acceptable salt of Compound of Formula I, to a patientin need of such treatment.

In another aspect, the invention provides a method for reducing bonepain due to metastatic bone lesions associated with lung cancer, breastcancer, melanoma, renal cell carcinoma, or thyroid cancer, comprisingadministering a therapeutically effective amount of a pharmaceuticalformulation to a patient in need of such treatment comprising Compoundof Formula I or the malate salt of Compound of Formula I or anotherpharmaceutically acceptable salt of Compound of Formula I, to a patientin need of such treatment.

In another aspect, the invention provides a method for treating orminimizing bone pain due to metastatic bone lesions associated with lungcancer, breast cancer, melanoma, renal cell carcinoma, or thyroidcancer, comprising administering a therapeutically effective amount of apharmaceutical formulation to a patient in need of such treatmentcomprising Compound of Formula I or the malate salt of Compound ofFormula I or another pharmaceutically acceptable salt of Compound ofFormula I, to a patient in need of such treatment.

In another aspect, the invention provides a method for preventing bonemetastases associated with lung cancer, breast cancer, melanoma, renalcell carcinoma, or thyroid cancer, comprising administering atherapeutically effective amount of a pharmaceutical formulation to apatient in need of such treatment comprising Compound of Formula I orthe malate salt of Compound of Formula I or another pharmaceuticallyacceptable salt of Compound of Formula I, to a patient in need of suchtreatment.

In another aspect, the invention provides a method for preventing bonemetastases in patients with lung cancer, breast cancer, melanoma, renalcell carcinoma, or thyroid cancer, who have not yet advanced tometastatic disease, comprising administering a therapeutically effectiveamount of a pharmaceutical formulation to a patient in need of suchtreatment comprising Compound of Formula I or the malate salt ofCompound of Formula I or another pharmaceutically acceptable salt ofCompound of Formula I, to a patient in need of such treatment.

In another aspect, the invention provides a method for extending theoverall survival in patients with lung cancer, breast cancer, melanoma,renal cell carcinoma, or thyroid cancer, comprising administering atherapeutically effective amount of a pharmaceutical formulation to apatient in need of such treatment comprising Compound of Formula I orthe malate salt of Compound of Formula I or another pharmaceuticallyacceptable salt of Compound of Formula I, to a patient in need of suchtreatment.

In another aspect, the invention provides a method for treating bonecancer pain in an individual comprising administering to the individualan effective amount of a Compound of Formula I or the malate salt ofCompound of Formula I or another pharmaceutically acceptable salt ofCompound of Formula I, to a patient in need of such treatment. In aspecific embodiment, the Compound of Formula I is Compound 1. In thisaspect, the bone cancer pain can originate from bone cancer,osteosarcoma, as well as from cancer metastasized to bone. Thus, in thisaspect, the bone cancer pain can be from the list including but notlimited to bone metastases from lung cancer, breast cancer, sarcoma, orrenal cancer.

In these and other aspects, the ability of the compound of Formula I totreat, ameliorate, or reduce the severity of bone metastases can bedetermined both qualitatively and quantitatively using variousphysiological markers, such as circulating biomarkers of bone turnover(ie bALP, CTx, and NTx), circulating tumor cell (CTC) counts, andimaging technologies. The imaging technologies include positron emissiontomography (PET) or computerized tomography (CT) and magnetic resonanceimaging. By using these imaging techniques, it is possible to monitorand quantify the reduction in tumor size and the reduction in the numberand size of bone lesions in response to treatment with the compound ofFormula I.

In these and other aspects, shrinkage of soft tissue and viscerallesions has been observed to result when the compound of Formula I isadministered to patients with CRPC. Moreover, administration of thecompound of Formula I leads to increases in hemoglobin concentration inpatients CRPC patients with anemia.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-C show the bone scan (FIG. 1A), bone scan response (FIG. 1B),and CT scan data (FIG. 1C) for Patient 1 having CRPC.

FIGS. 2A-C show the bone scan (FIG. 2A), bone scan response (FIG. 2B),and CT scan data (FIG. 2C) for Patient 2 having CRPC.

FIGS. 3A-B show the bone scan (FIG. 3A), bone scan response (FIG. 3B)for Patient 3 having CRPC.

FIGS. 4A and B shows the bone scan (FIG. 4A), bone scan response (FIG.4B) for a Patient having renal cell carcinoma with bone metastases.

FIGS. 5A and 5B shows the bone scan (FIG. 5A), bone scan response (FIG.5B) for a Patient having melanoma with bone metastases.

FIG. 6 shows a CT scan of a bone metastasis from a patient withdifferentiated thyroid cancer before (FIG. 6A) and after (FIG. 6B)treatment.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning Ac Acetyl bALP Bone-specific alkaline phosphataseBr Broad ° C. Degrees Celsius c- Cyclo CBZ CarboBenZoxy =benzyloxycarbonyl CTx Cross-linked C-terminal telopeptides of type-1collagen d Doublet dd Doublet of doublet dt Doublet of triplet DCMDichloromethane DME 1,2-dimethoxyethane DMF N,N-Dimethylformamide DMSOdimethyl sulfoxide Dppf 1,1′-bis(diphenylphosphano)ferrocene EI ElectronImpact ionization G Gram(s) h or hr Hour(s) HPLC High pressure liquidchromatography L Liter(s) M Molar or molarity m Multiplet MgMilligram(s) MHz Megahertz (frequency) Min Minute(s) mL Milliliter(s) μLMicroliter(s) μM Micromole(s) or micromolar mM Millimolar MmolMillimole(s) Mol Mole(s) MS Mass spectral analysis N Normal or normalitynM Nanomolar NMR Nuclear magnetic resonance spectroscopy NTxCross-linked N-terminal telopeptides of type-1 collagen q Quartet RTRoom temperature s Singlet t or tr Triplet TFA Trifluoroacetic acid THFTetrahydrofuran TLC Thin layer chromatography

The symbol “—” means a single bond, “=” means a double bond.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₁CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted hydrogen(for example the —NH— in the formula above), implied hydrogen (forexample as in the formula above, where the hydrogens are not shown butunderstood to be present), or expressly defined hydrogen (for examplewhere in the formula above, “Z” equals ═CH—) from one of the ring atoms,so long as a stable structure is formed. In the example depicted, the“R” group may reside on either the 5-membered or the 6-membered ring ofthe fused ring system. When a group “R” is depicted as existing on aring system containing saturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In another embodiment the patient is a mammal, and inanother embodiment the patient is human.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference orS. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 both of which are incorporated herein by reference.

Examples of pharmaceutically acceptable acid addition salts includethose formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; as wellas organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, malic acid, citric acid, benzoicacid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid and the like.

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)the alkyl group is a straight or branched chain. Acceptable esters alsoinclude cycloalkyl esters and arylalkyl esters such as, but not limitedto benzyl. Examples of pharmaceutically acceptable amides of thecompounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. A therapeutically effective amount is intended to includean amount of a compound alone or in combination with other activeingredients effective to modulate c-Met, and/or VEGFR2, or effective totreat or prevent cancer. The amount of a compound of the invention whichconstitutes a “therapeutically effective amount” will vary depending onthe compound, the disease state and its severity, the age of the patientto be treated, and the like. The therapeutically effective amount can bedetermined by one of ordinary skill in the art having regard to theirknowledge and to this disclosure.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) preventing the disease, disorder, or syndrome fromoccurring in a human, i.e. causing the clinical symptoms of the disease,disorder, or syndrome not to develop in an animal that may be exposed toor predisposed to the disease, disorder, or syndrome but does not yetexperience or display symptoms of the disease, disorder, or syndrome;(ii) inhibiting the disease, disorder, or syndrome, i.e., arresting itsdevelopment; and (iii) relieving the disease, disorder, or syndrome,i.e., causing regression of the disease, disorder, or syndrome. As isknown in the art, adjustments for systemic versus localized delivery,age, body weight, general health, sex, diet, time of administration,drug interaction and the severity of the condition may be necessary, andwill be ascertainable with routine experience.

Embodiments

In one embodiment the compound of Formula I is the compound of FormulaIa:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is halo;

R² is halo; and

Q is CH or N.

In another embodiment, the compound of Formula I is Compound 1:

or a pharmaceutically acceptable salt thereof. As indicated previously,compound I is referred to herein asN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.WO 2005/030140 discloses Compound 1 and describes how it is made(Example 12, 37, 38, and 48) and also discloses the therapeutic activityof this compound to inhibit, regulate and/or modulate the signaltransduction of kinases, (Assays, Table 4, entry 289). Example 48 is onparagraph [0353] in WO 2005/030140.

In other embodiments, the compound of Formula I, Ia, or Compound 1, or apharmaceutically acceptable salt thereof, is administered as apharmaceutical composition, wherein the pharmaceutical compositionadditionally comprises a pharmaceutically acceptable carrier, excipient,or diluent. In a specific embodiment, the Compound of Formula I isCompound 1.

The compound of Formula I, Formula Ia, and Compound I, as describedherein, includes both the recited compounds as well as individualisomers and mixtures of isomers. In each instance, the compound ofFormula I includes the pharmaceutically acceptable salts, hydrates,and/or solvates of the recited compounds and any individual isomers ormixture of isomers thereof.

In other embodiments, the compound of Formula I, Ia, or Compound 1 canbe the malate salt. The malate salt of the Compound of Formula I and ofCompound 1 is disclosed in PCT/US2010/021194 and 61/325,095.

In other embodiments, the compound of Formula I, Ia, or 1 can be the(D)-malate salt.

In other embodiments, the compound of Formula I, Ia, or 1 can be malatesalt.

In other embodiments, the compound of Formula I, Ia, or 1 can be the(L)-malate salt.

In other embodiments, Compound 1 can be (D)-malate salt.

In other embodiments, Compound 1 can be the (L)-malate salt.

In another embodiment, the malate salt of Compound 1 is in thecrystalline N-1 form of the (L) malate salt and/or the (D) malate saltof the Compound 1 as disclosed in U.S. patent Application Ser. No.61/325,095. Also see WO 2008/083319 for the properties of crystallineenantiomers, including the N-1 and/or the N-2 crystalline forms of themalate salt of Compound 1. Methods of making and characterizing suchforms are fully described in PCT/US10/21194, which is incorporatedherein by reference in its entirety.

In another embodiment, the invention is directed to a method forameliorating the symptoms of bone metastases, comprising administeringto a patient in need of such treatment a therapeutically effectiveamount of a compound of Formula I in any of the embodiments disclosedherein. In a specific embodiment, the Compound of Formula I is Compound1.

In another embodiment, the invention is directed to a method fortreating pain associated with bone metastases, comprising administeringto a patient in need of such treatment a therapeutically effectiveamount of a compound of Formula I in any of the embodiments disclosedherein. In a specific embodiment, the Compound of Formula I is Compound1.

In another embodiment, the compound of Formula I is administeredpost-taxotere treatment. In a specific embodiment, the Compound ofFormula I is Compound 1.

In another embodiment, the compound of Formula I is as effective or moreeffective than mitoxantrone plus prednisone. In a specific embodiment,the Compound of Formula I is Compound 1.

In another embodiment, the Compound of Formula I, Ia, or Compound 1 or apharmaceutically acceptable salt thereof is administered orally oncedaily as a tablet or capsule.

In another embodiment, Compound 1 is administered orally as its freebase or malate salt as a capsule or tablet.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing upto 100 mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing100 mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 95mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 90mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 85mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 80mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 75mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 70mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 65mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 60mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 55mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 50mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 45mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 40mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 30mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 25mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 20mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 15mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 10mg of Compound 1.

In another embodiment, Compound 1 is administered orally once daily asits free base or as the malate salt as a capsule or tablet containing 5mg of Compound 1.

In another embodiment, Compound 1 is administered as its free base ormalate salt orally once daily as a tablet as provided in the followingtable.

Ingredient (% w/w) Compound 1 31.68 Microcrystalline Cellulose 38.85Lactose anhydrous 19.42 Hydroxypropyl Cellulose 3.00 CroscarmelloseSodium 3.00 Total Intra-granular 95.95 Silicon dioxide, Colloidal 0.30Croscarmellose Sodium 3.00 Magnesium Stearate 0.75 Total 100.00

In another embodiment, Compound 1 is administered orally as its freebase or malate salt once daily as a tablet as provided in the followingtable.

Ingredient (% w/w) Compound 1 25.0-33.3 Microcrystalline Cellulose q.sHydroxypropyl Cellulose 3 Poloxamer 0-3 Croscarmellose Sodium 6.0Colloidal Silicon Dioxide 0.5 Magnesium Stearate 0.5-1.0 Total 100

In another embodiment, Compound 1 is administered orally as its freebase or malate salt once daily as a tablet as provided in the followingtable.

Theoretical Quantity (mg/unit Ingredient dose) Compound 1 100.0Microcrystalline Cellulose PH- 155.4 102 Lactose Anhydrous 60M 77.7Hydroxypropyl Cellulose, EXF 12.0 Croscarmellose Sodium 24 ColloidalSilicon Dioxide 1.2 Magnesium Stearate (Non- 3.0 Bovine) Opadry Yellow16.0 Total 416

Any of the tablet formulations provided above can be adjusted accordingto the dose of Compound 1 desired. Thus, the amount of each of theformulation ingredients can be proportionally adjusted to provide atable formulation containing various amounts of Compound 1 as providedin the previous paragraphs. In another embodiment, the formulations cancontain 20, 40, 60, or 80 mg of Compound 1.

Administration

Administration of the compound of Formula I, Formula Ia, or Compound 1,or a pharmaceutically acceptable salt thereof, in pure form or in anappropriate pharmaceutical composition, can be carried out via any ofthe accepted modes of administration or agents for serving similarutilities. Thus, administration can be, for example, orally, nasally,parenterally (intravenous, intramuscular, or subcutaneous), topically,transdermally, intravaginally, intravesically, intracistemally, orrectally, in the form of solid, semi-solid, lyophilized powder, orliquid dosage forms, such as for example, tablets, suppositories, pills,soft elastic and hard gelatin dosages (which can be in capsules ortablets), powders, solutions, suspensions, or aerosols, or the like,specifically in unit dosage forms suitable for simple administration ofprecise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of Formula I as the/an active agent, and, inaddition, may include carriers and adjuvants, etc.

Adjuvants include preserving, wetting, suspending, sweetening,flavoring, perfuming, emulsifying, and dispensing agents. Prevention ofthe action of microorganisms can be ensured by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, and the like. It may also be desirable to include isotonic agents,for example sugars, sodium chloride, and the like. Prolonged absorptionof the injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the compound of Formula Imay also contain minor amounts of auxiliary substances such as wettingor emulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

The choice of composition depends on various factors such as the mode ofdrug administration (e.g., for oral administration, compositions in theform of tablets, pills or capsules) and the bioavailability of the drugsubstance. Recently, pharmaceutical compositions have been developedespecially for drugs that show poor bioavailability based upon theprinciple that bioavailability can be increased by increasing thesurface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical composition having particles in thesize range from 10 to 1,000 nm in which the active material is supportedon a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684describes the production of a pharmaceutical composition in which thedrug substance is pulverized to nanoparticles (average particle size of400 nm) in the presence of a surface modifier and then dispersed in aliquid medium to give a pharmaceutical composition that exhibitsremarkably high bioavailability.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One specific route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,the compound of Formula I, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administration are, for example, suppositoriesthat can be prepared by mixing the compound of Formula I with, forexample, suitable non-irritating excipients or carriers such as cocoabutter, polyethyleneglycol or a suppository wax, which are solid atordinary temperatures but liquid at body temperature and therefore, meltwhile in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of the compound of Formula Iinclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic compositions, eye ointments, powders, and solutionsare also contemplated as being within the scope of this disclosure.

Compressed gases may be used to disperse the compound of Formula I inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of Formula I, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of Formula I,Formula Ia, or Compound 1, or a pharmaceutically acceptable saltthereof, with the rest being suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known or will beapparent to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof, for treatment of adisease-state in accordance with the teachings of this disclosure.

The compounds of this disclosure, or their pharmaceutically acceptablesalts or solvates, are administered in a therapeutically effectiveamount which will vary depending upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of the compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular disease-states, and the hostundergoing therapy. The compound of Formula I, Formula Ia, or Compound1, can be administered to a patient at dosage levels in the range ofabout 0.1 to about 1,000 mg per day. For a normal human adult having abody weight of about 70 kilograms, a dosage in the range of about 0.01to about 100 mg per kilogram of body weight per day is an example. Thespecific dosage used, however, can vary. For example, the dosage candepend on a number of factors including the requirements of the patient,the severity of the condition being treated, and the pharmacologicalactivity of the compound being used. The determination of optimumdosages for a particular patient is well known to one of ordinary skillin the art.

In other embodiments, the compound of Formula I, Formula Ia, or Compound1, can be administered to the patient concurrently with other cancertreatments. Such treatments include other cancer chemotherapeutics,hormone replacement therapy, radiation therapy, or immunotherapy, amongothers. The choice of other therapy will depend on a number of factorsincluding the metabolic stability and length of action of the compound,the age, body weight, general health, sex, diet, mode and time ofadministration, rate of excretion, drug combination, the severity of theparticular disease-states, and the host undergoing therapy.

Preparation of Compound 1 Preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt thereof

The synthetic route used for the preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt thereof is depicted in Scheme 1.

Preparation of 4-Chloro-6,7-dimethoxy-quinoline

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol(10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated toapproximately 65° C. and phosphorus oxychloride (POCl₃, 50.0 kg) wasadded. After the addition of POCl₃, the temperature of the reactionmixture was raised to approximately 80° C. The reaction was deemedcomplete (approximately 9.0 hours) when less than 2 percent of thestarting material remained (in process high-performance liquidchromotography [HPLC] analysis). The reaction mixture was cooled toapproximately 10° C. and then quenched into a chilled solution ofdichloromethane (DCM, 238.0 kg), 30 percent NH₄OH (135.0 kg), and ice(440.0 kg). The resulting mixture was warmed to approximately 14° C.,and phases were separated. The organic phase was washed with water (40.0kg) and concentrated by vacuum distillation with the removal of solvent(approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was addedto the batch, and the mixture was cooled to approximately 10° C., duringwhich time the product crystallized out. The solids were recovered bycentrifugation, washed with n heptane (20.0 kg), and dried atapproximately 40° C. to afford the title compound (8.0 kg).

Preparation of 6,7-Dimethyl-4-(4-nitro-phenoxy)-quinoline

A reactor was sequentially charged with 4-chloro-6,7-dimethoxy-quinoline(8.0 kg), 4 nitrophenol (7.0 kg), 4 dimethylaminopyridine (0.9 kg), and2,6-lutidine (40.0 kg). The reactor contents were heated toapproximately 147° C. When the reaction was complete (less than 5%starting material remaining as determined by in process HPLC analysis,approximately 20 hours), the reactor contents were allowed to cool toapproximately 25° C. Methanol (26.0 kg) was added, followed by potassiumcarbonate (3.0 kg) dissolved in water (50.0 kg). The reactor contentswere stirred for approximately 2 hours. The resulting solid precipitatewas filtered, washed with water (67.0 kg), and dried at 25° C. forapproximately 12 hours to afford the title compound (4.0 kg).

Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine

A solution containing potassium formate (5.0 kg), formic acid (3.0 kg),and water (16.0 kg) was added to a mixture of6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10% palladium oncarbon (50 percent water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) thathad been heated to approximately 60° C. The addition was carried outsuch that the temperature of the reaction mixture remained approximately60° C. When the reaction was deemed complete as determined usingin-process HPLC analysis (less than 2 percent starting materialremaining, typically 1.5-15 hours), the reactor contents were filtered.The filtrate was concentrated by vacuum distillation at approximately35° C. to half of its original volume, which resulted in theprecipitation of the product. The product was recovered by filtration,washed with water (12.0 kg), and dried under vacuum at approximately 50°C. to afford the title compound (3.0 kg; 97 percent AUC).

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

Triethylamine (8.0 kg) was added to a cooled (approximately 4° C.)solution of commercially available cyclopropane-1,1-dicarboxylic acid(10.0 kg) in THF (63.0 kg) at a rate such that the batch temperature didnot exceed 10° C. The solution was stirred for approximately 30 minutes,and then thionyl chloride (9.0 kg) was added, keeping the batchtemperature below 10° C. When the addition was complete, a solution of4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such thatthe batch temperature did not exceed 10° C. The mixture was stirred forapproximately 4 hours and then diluted with isopropyl acetate (87.0 kg).This solution was washed sequentially with aqueous sodium hydroxide (2.0kg dissolved in 50.0 L of water), water (40.0 L), and aqueous sodiumchloride (10.0 kg dissolved in 40.0 L of water). The organic solutionwas concentrated by vacuum distillation followed by the addition ofheptane, which resulted in the precipitation of solid. The solid wasrecovered by centrifugation and then dried at approximately 35° C. undervacuum to afford the title compound (10.0 kg).

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

Oxalyl chloride (1.0 kg) was added to a solution of1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (2.0 kg) in amixture of THF (11 kg) and N,N-dimethylformamide (DMF; 0.02 kg) at arate such that the batch temperature did not exceed 30° C. This solutionwas used in the next step without further processing.

Preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

The solution from the previous step containing1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added toa mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg),and potassium carbonate (4.0 kg) in THF (27.0 kg), and water (13.0 kg)at a rate such that the batch temperature did not exceed 30° C. When thereaction was complete (approximately 10 minutes), water (74.0 kg) wasadded. The mixture was stirred at 15 to 30° C. for approximately 10hours, which resulted in the precipitation of the product. The productwas recovered by filtration, washed with a pre made solution of THF(11.0 kg) and water (24.0 kg), and dried at approximately 65° C. undervacuum for approximately 12 hours to afford the title compound (freebase, 5.0 kg). ¹H NMR (400 MHz, d₆-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H),8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25(m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS:M+H=502.

Preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(L) malate salt

A solution of L-malic acid (2.0 kg) in water (2.0 kg) was added to asolution of Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide free base (1 5, 5.0 kg) in ethanol, maintaininga batch temperature of approximately 25° C. Carbon (0.5 kg) and thiolsilica (0.1 kg) were then added, and the resulting mixture was heated toapproximately 78° C., at which point water (6.0 kg) was added. Thereaction mixture was then filtered, followed by the addition ofisopropanol (38.0 kg). The reaction mixture was allowed to cool toapproximately 25° C. The product was recovered by filtration and washedwith isopropanol (20.0 kg) and dried at approximately 65° C. to affordthe title compound (5.0 kg).

An alternative route that for the preparation of Compound 1 is depictedin Scheme 2.

Preparation of 4-Chloro-6,7-dimethoxy-quinoline

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol(47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heatedto approximately 60° C. and phosphorus oxychloride (POCl₃, 130.6 kg) wasadded. After the addition of POCl₃, the temperature of the reactionmixture was raised to approximately 77° C. The reaction was deemedcomplete (approximately 13 hours) when less than 3 percent of thestarting material remained (in-process high-performance liquidchromatography [HPLC] analysis). The reaction mixture was cooled toapproximately 2 to 7° C. and then quenched into a chilled solution ofdichloromethane (DCM, 482.8 kg), 26 percent NH₄OH (251.3 kg), and water(900 L). The resulting mixture was warmed to approximately 20 to 25° C.,and phases were separated. The organic phase was filtered through a bedof AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washedwith DCM (118.9 kg). The combined organic phase was washed with brine(282.9 kg) and mixed with water (120 L). The phases were separated andthe organic phase was concentrated by vacuum distillation with theremoval of solvent (approximately 95 L residual volume). DCM (686.5 kg)was charged to the reactor containing organic phase and concentrated byvacuum distillation with the removal of solvent (approximately 90 Lresidual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then chargedand the temperature of the mixture was adjusted to −20 to 25° C. andheld for 2.5 hours. This resulted in solid precipitate, which was thenfiltered, washed with n-heptane (92.0 kg), and dried on a filter atapproximately 25° C. under nitrogen to afford the title compound. (35.6kg).

Preparation of 4-(6,7-Dimethoxy-1-quinoline-4-yloxy)-phenylamine

4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline(35.3 kg), sodium t-butoxide, (21.4 kg) and DMA (167.2 kg) at 20 to 25°C. This mixture was then heated to 100 to 105° C. for approximately 13hours. After the reaction was deemed complete as determined usingin-process HPLC analysis (less than 2 percent starting materialremaining), the reactor contents were cooled at 15 to 20° C. and water(pre-cooled, 2 to 7° C., 587 L) charged at a rate to maintain 15 to 30°C. temperature. The resulting solid precipitate was filtered, washedwith a mixture of water (47 L) and DMA (89.1 kg) and finally with water(214 L). The filter cake was then dried at approximately 25° C. onfilter to yield crude 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine(59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed(approximately 75° C.) in a mixture of tetrahydrofuran (THF, 211.4 kg)and DMA (108.8 kg) for approximately 1 hour and then cooled to 0 to 5°C. and aged for approximately 1 hour after which time the solid wasfiltered, washed with THF (147.6 kg), and dried on a filter under vacuumat approximately 25° C. to yield4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg).

Alternative Preparation of4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine

4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-Aminophenol (30.8 kg)and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 wt percent inTHF) were charged to a reactor, followed by N,N-dimethylacetamide (DMA,293.3 kg). This mixture was then heated to 105 to 115° C. forapproximately 9 hours. After the reaction was deemed complete asdetermined using in-process HPLC analysis (less than 2 percent startingmaterial remaining), the reactor contents were cooled at 15 to 25° C.,and water (315 kg) was added over a two hour period while maintainingthe temperature between 20 and 30° C. The reaction mixture was thenagitated for an additional hour at 20 to 25° C. The crude product wascollected by filtration and washed with a mixture of water (88 kg) andDMA (82.1 kg), followed by water (175 kg). The product was dried on afilter drier for 53 hours. The LOD showed less than 1 percentweight/weight (w/w).

In an alternative procedure, 1.6 equivalents of sodium tert-pentoxidewere used, and the reaction temperature was increased from 110 to 120°C. In addition, the cool down temperature was increased to 35 to 40° C.,and the starting temperature of the water addition was adjusted to 35 to40° C., with an allowed exotherm to 45° C.

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

Triethylamine (19.5 kg) was added to a cooled (approximately 5° C.)solution of cyclopropane-1,1-dicarboxylic acid (24.7 kg) in THF (89.6kg) at a rate such that the batch temperature did not exceed 5° C. Thesolution was stirred for approximately 1.3 hours, and then thionylchloride (23.1 kg) was added, keeping the batch temperature below 10° C.When the addition was complete, the solution was stirred forapproximately 4 hours keeping the temperature below 10° C. A solution of4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate suchthat the batch temperature did not exceed 10° C. The mixture was stirredfor approximately 10 hours, after which the reaction was deemedcomplete. The reaction mixture was then diluted with isopropyl acetate(218.1 kg). This solution was washed sequentially with aqueous sodiumhydroxide (10.4 kg, 50% dissolved in 119 L of water), further dilutedwith water (415 L), then with water (100 L), and finally with aqueoussodium chloride (20.0 kg dissolved in 100 L of water). The organicsolution was concentrated by vacuum distillation (100 L residual volume)below 40° C., followed by the addition of n-heptane (171.4 kg), whichresulted in the precipitation of solid. The solid was recovered byfiltration and washed with n-Heptane (102.4 kg), resulting in wet crude,1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). Thecrude, 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid wasdissolved in methanol (139.7 kg) at approximately 25° C., followed bythe addition of water (320 L), resulting in slurry which was recoveredby filtration, washed sequentially with water (20 L) and n-heptane(103.1 kg), and then dried on the filter at approximately 25° C. undernitrogen to afford the title compound (25.4 kg).

Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

Oxalyl chloride (12.6 kg) was added to a solution of1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in amixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23 kg) at arate such that the batch temperature did not exceed 25° C. This solutionwas used in the next step without further processing.

Alternative Preparation of1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride

A reactor was charged with1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (35 kg), DMF(344 g), and THF (175 kg). The reaction mixture was adjusted to 12 to17° C., and then to the reaction mixture was charged 19.9 kg of oxalylchloride over a period of 1 hour. The reaction mixture was left stirringat 12 to 17° C. for 3 to 8 hours. This solution was used in the nextstep without further processing.

Preparation of Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide

The solution from the previous step containing1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added toa mixture of compound 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine(23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water(116 L) at a rate such that the batch temperature did not exceed 30° C.When the reaction was complete (in approximately 20 minutes), water (653L) was added. The mixture was stirred at 20 to 25° C. for approximately10 hours, which resulted in the precipitation of the product. Theproduct was recovered by filtration, washed with a pre-made solution ofTHF (68.6 kg) and water (256 L), and dried first on a filter undernitrogen at approximately 25° C. and then dried at approximately 45° C.under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculatedbased on LOD).

Alternative Preparation of Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinolone-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide

A reactor was charged with4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent),followed by THF (412.9 kg). To the reaction mixture was charged asolution of K₂CO₃ (48.3 g) in water (169 kg). The acid chloride solutiondescribed in the Alternative Preparation of1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride above wastransferred to the reactor containing4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine while maintaining thetemperature between 20 to 30° C. over a minimum of two hours. Thereaction mixture was stirred at 20 to 25° C. for a minimum of threehours. The reaction temperature was then adjusted to 30 to 25° C., andthe mixture was agitated. The agitation was stopped and the phases ofthe mixture were allowed to separate. The lower aqueous phase wasremoved and discarded. Water (804 kg) was added to the remaining upperorganic phase. The reaction was left stirring at 15 to 25° C. for aminimum of 16 hours.

The product precipitated. The product was filtered and washed with amixture of water (179 kg) and THF (157.9 kg) in two portions. The crudeproduct was dried under a vacuum for at least two hours. The driedproduct was then taken up in THF (285.1 kg). The resulting suspensionwas transferred to reaction vessel and agitated until the suspensionbecame a clear (dissolved) solution, which required heating to 30 to 35°C. for approximately 30 minutes. Water (456 kg) was then added to thesolution, as well as SDAG-1 (20 kg) ethanol (ethanol denatured withmethanol over two hours). The mixture was agitated at 15-25° C. for atleast 16 hours. The product was filtered and washed with a mixture ofwater (143 kg) and THF (126.7 kg) in two portions. The product was driedat a maximum temperature set point of 40° C.

In an alternative procedure, the reaction temperature during acidchloride formation was adjusted to 10 to 15° C. The recrystallizationtemperature was changed from 15 to 25° C. to 45 to 50° C. for 1 hour andthen cooled to 15 to 25° C. over 2 hours.

Preparation of Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide, (L) malate salt

Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (13.3 kg), L-malic acid (4.96 kg), methyl ethylketone (MEK; 188.6 kg), and water (37.3 kg) were charged to a reactor,and the mixture was heated to reflux (approximately 74° C.) forapproximately 2 hours. The reactor temperature was reduced to 50 to 55°C., and the reactor contents were filtered. These sequential stepsdescribed above were repeated two more times starting with similaramounts of cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6kg), and water (37.2 kg). The combined filtrate was azeotropically driedat atmospheric pressure using MEK (1133.2 kg) (approximate residualvolume 711 L; KF≦0.5 w/w) at approximately 74° C. The temperature of thereactor contents was reduced to 20 to 25° C. and held for approximately4 hours, resulting in solid precipitate which was filtered, washed withMEK (448 kg), and dried under vacuum at 50° C. to afford the titlecompound (45.5 kg).

Alternative Preparation of Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide, (L) malate salt

Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg methylethyl ketone, and 129.1 kg water (37.3 kg) were charged to a reactor,and the mixture was heated 50 to 55° C. for approximately 1 to 3 hours,and then at 55 to 60° C. for an additional 4 to 5 hours. The mixture wasclarified by filtration through a 1 μm cartridge. The reactortemperature was adjusted to 20 to 25° C. and vacuum distilled with avacuum at 150-200 mm Hg with a maximum jacket temperature of 55° C. tothe volume range of 558-731 L.

The vacuum distillation was performed two more times with the charge of380 kg and 380.2 kg methyl ethyl ketone, respectively. After the thirddistillation, the volume of the batch was adjusted to 18 volume/weight(v/w) of cyclopropane-,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide by charging methyl ethyl ketone (159.9 kg) togive a total volume of 880 L. An additional vacuum distillation wascarried out by adjusting methyl ethyl ketone (245.7 kg). The reactionmixture was left with moderate agitation at 20 to 25° C. for at least 24hours. The product was filtered and washed with methyl ethyl ketone(415.1 kg) in three portions. The product was dried under a vacuum withthe jacket temperature set point at 45° C.

In an alternative procedure, the order of addition was changes so that asolution of L-malic acid (17.7 kg) dissolved in water (129.9 kg) wasadded to cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]amide(4-fluoro-phenyl)-amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

Use of a Compound of Formula I to Treat Cancer

The MET and VEGF signaling pathways appear to play important roles inosteoblast and osteoclast function. Strong immunohistochemical stainingof MET has been observed in both cell types in developing bone. HGF andMET are expressed by osteoblasts and osteoclasts in vitro and mediatecellular responses such as proliferation, migration, and expression ofALP. Secretion of HGF by osteoblasts has been proposed as a key factorin osteoblast/osteoclast coupling, and in the development of bonemetastases by tumor cells that express MET. Osteoblasts and osteoclastsalso express VEGF and its receptors, and VEGF signaling in these cellsis involved in potential autocrine and/or paracrine feedback mechanismsregulating cell migration, differentiation, and survival.

Compound 1 is an orally bioavailable multitargeted tyrosine kinaseinhibitor with potent activity against MET and VEGFR2. Compound 1suppresses MET and VEGFR2 signaling, rapidly induces apoptosis ofendothelial cells and tumor cells, and causes tumor regression inxenograft tumor models. Compound 1 also significantly reduces tumorinvasiveness and metastasis and substantially improves overall survivalin a murine pancreatic neuroendocrine tumor model. In a phase 1 clinicalstudy, Compound 1 was generally well-tolerated, with fatigue, diarrhea,anorexia, rash, and palmar-plantar erythrodysesthesia being the mostcommonly observed adverse events.

Case Study 1

Compound 1 is an orally bioavailable multitargeted tyrosine kinaseinhibitor with potent activity against MET and VEGFR2. Compound 1suppresses MET and VEGFR2 signaling, rapidly induces apoptosis ofendothelial cells and tumor cells, and causes tumor regression inxenograft tumor models. Compound 1 also significantly reduces tumorinvasiveness and metastasis and substantially improves overall survivalin a murine pancreatic neuroendocrine tumor model. In a phase 1 clinicalstudy, Compound 1 was generally well-tolerated, with fatigue, diarrhea,anorexia, rash, and palmar-plantar erythrodysesthesia being the mostcommonly observed adverse events.

Based on target rationale and observed antitumor activity in clinicalstudies, an adaptive phase 2 trial was undertaken in multipleindications including CRPC(http://clinicaltrials.gov/ct2/results?term=NCT00940225 for StudyNCT00940225 last visited Sep. 20, 2011)), in which Compound 1 wasadministered as a 100 mg dose to patients. The findings in the firstthree CRPC patients with evidence of bone metastases on bone scanenrolled to this study are described in the following Case Studies.

Baseline characteristics for patients 1-3 are summarized in Table 1.

TABLE 1 Summary of Baseline Characteristics and Preliminary BestResponses for CRPC Patients Treated with Compound 1. Patient 1 Patient 2Patient 3 Baseline Characteristics Age (years) 77 73 66 Diagnosis 19932009 2009 ECOG 1 0 1 performance status Disease location(s) Lung, LN,bone Liver, LN, bone LN, bone Prior cancer Radical Radiation to CAB,therapies prostatectomy, pubic ramus and docetaxel radiation toacetabulum, prostate bed, CAB CAB, DES, docetaxel Bisphophonates No NoYes Narcotics Yes No No Pain Yes Yes Yes PSA (ng/mL) 430.4 14.7 2.8 tALP(U/L) 689 108 869 Hemoglobin (g/dL) 13.5 13.3 10.2 Summary of BestResponses Tumor response −41% −20% −51% Bone scan Complete ImprovementNear resolution resolution Pain Improvement Pain-free Pain-free PSA −78%+61% −57% tALP −77%  −6% −77% Hemoglobin (g/dL) +1.4 +1.8 +2.2 ADT,androgen-deprivation therapy; CAB, combined androgen blockade(leuprolide + bicalutamide); DES, diethylstilbestrol; LN, lymph node;PSA, prostate-specific antigen; tALP, total alkaline phosphatase.

Patient 1 was diagnosed with localized prostate cancer in 1993 andtreated with radical prostatectomy (Gleason score unavailable; PSA, 0.99ng/mL). In 2000, local disease recurrence was treated with radiationtherapy. In 2001, combined androgen blockade (CAB) with leuprolide andbicalutamide was initiated for rising PSA (3.5 ng/mL). In 2006,diethystillbestrol (DES) was administered briefly. In 2007, 6 cycles ofdocetaxel were given for new lung metastases. Rising PSA wasunresponsive to antiandrogen withdrawal. Androgen ablation therapy wascontinued until clinical progression. In October 2009, bone metastasisto the spine associated with impingement on the spinal cord and backpain, was treated with radiation therapy (37.5 Gy). In February 2010, abone scan was performed due to increasing bone pain and showed diffuseuptake of radiotracer in the axial and appendicular skeleton. A CT scanrevealed new pulmonary and mediastinal lymph node metastases. PSA was430.4 ng/mL.

Patient 2 was diagnosed in April of 2009 after presenting with apathologic fracture (Gleason score, 4+5=9; PSA, 45.34 ng/mL). Bone scanshowed uptake of radiotracer in the left iliac wing, left sacroiliacjoint, femoral head, and the pubic symphysis. Biopsy of the left pubicramus confirmed metastatic adenocarcinoma with mixed lytic and blasticlesions. CAB with leuprolide and bicalutamide and radiation therapy (8Gy) to the left pubic ramus and acetabulum resulted in bone pain reliefand PSA normalization. Rising PSA in November 2009 (16 ng/mL) wasunresponsive to antiandrogen withdrawal. In February 2010, bone scanshowed multiple foci throughout the axial and appendicular skeleton. ACT scan revealed retroperitoneal lymph node enlargement and livermetastases (PSA, 28.1 ng/mL). Further progression of disease was markedby recurrent bone pain, new lung and hepatic metastases.

Patient 3 was diagnosed in April 2009 after presenting with right hippain (Gleason score, 4+5=9; PSA, 2.6 ng/mL). Bone scan showed uptake ofradiotracer at multiple sites throughout the axial and appendicularskeleton. A CT scan revealed retroperitoneal, common iliac, andsupraclavicular adenopathy. CAB with leuprolide and bicalutamide wasinitiated. The patient received 6 cycles of docetaxel through December2009. Following treatment, a bone scan showed no changes. A CT scanrevealed near resolution of the retroperitoneal and common iliacadenopathy. In March 2010, PSA began to rise, and bone pain worsened. Arepeat bone scan showed new foci, and a CT scan showed an increase inthe retroperitoneal, para-aortic, and bilateral common iliac adenopathy.Rising PSA in April 2010 (2.8 ng/mL) and increasing bone pain wereunresponsive to antiandrogen withdrawal.

Results

All patients provided informed consent before study screening.

Patient 1 started Compound 1 on Feb. 12, 2010. Four weeks later,significant reduction in bone pain was reported. At Week 6, bone scanshowed a dramatic decrease in radiotracer uptake by bone metastases(FIG. 1A). A CT scan showed a partial response (PR) with a 33% decreasein measurable target lesions (FIG. 1C). At Week 12, near completeresolution of bone lesions and a 44% decrease in target lesions wasobserved and was stable through Week 18. Corresponding with the bonescan response, after an initial rise, serum tALP levels decreased from689 U/L at baseline to 159 U/L at Week 18 (FIG. 1B and Table 1). Inaddition, there was an increase in hemoglobin of 1.4 g/dL at Week 2compared with baseline (Table 1). PSA decreased from 430 ng/mL atbaseline to 93.5 ng/mL at Week 18 (FIG. 1B and Table 1). The patient wason open-label treatment through Week 18 when he withdrew afterdeveloping Grade 3 diarrhea.

Patient 2 started Compound 1 on Mar. 31, 2010. At Week 4, reduction inbone pain was reported. At Week 6, bone scan showed a slight flair inradiotracer uptake by bone lesions (FIG. 2A), and a CT scan showed a 13%decrease in target lesions (FIG. 2C). At Week 12, a substantialreduction of radiotracer uptake (FIG. 2A) and a 20% decrease inmeasurable disease were observed (Table 1). After randomization toplacebo at Week 12 the patient developed severe bone pain and sacralnerve root impingement. Radiation to the spine was administered, and thepatient crossed over to open-label Compound 1 treatment at Week 15.Serum tALP levels were within the normal range (101-144 U/L) (FIG. 2B).Hemoglobin increased by 1.8 g/dL at Week 12 compared with baseline(Table 1). PSA peaked at close to 6-fold of baseline by Week 16, butthen decreased to 2-fold of baseline by Week 18 subsequent to crossingover to Compound 1 from placebo (FIG. 2B and Table 1). The patientcontinues on Compound 1 treatment as of September 2010.

Patient 3 started Compound 1 on Apr. 26, 2010. After three weeks acomplete resolution of pain was reported. At Week 6, bone scan showed adramatic reduction in radiotracer uptake (FIG. 3A), and a CT scan showeda PR with a 43% decrease in measurable target lesions. At Week 12 acomplete resolution of bone lesions on bone scan (FIG. 3A) and a 51%decrease in measurable disease were observed (Table 1 and FIG. 3B)).After an initial rise, serum tALP levels steadily decreased, with tALPat 869 U/L at baseline and 197 U/L at Week 18 (FIG. 3B and Table 1).Hemoglobin increased 2.2 g/dL at Week 2 compared with baseline (Table1). PSA decreased from 2.4 ng/mL at screening to 1.2 ng/mL at Week 18(FIG. 3B and Table 1). The patient continues on Compound 1 treatment asof September 2010.

Discussion

All three patients experienced a striking decrease in uptake ofradiotracer on bone scan upon treatment with Compound 1. These findingswere accompanied by substantial reductions in bone pain and evidence ofresponse or stabilization in soft tissue lesions during therapy withCompound 1. The onset of the effect was very rapid in two of thepatients, with substantial improvement or near resolution of bone scanand improvement in pain occurring in the first 6 weeks. In the thirdpatient, an apparent flare in the bone scan was observed at 6 weeks,followed by improvement by 12 weeks. To our knowledge, such acomprehensive and rapid impact on both osseous and soft tissue diseasehas not been observed in this patient population.

Uptake of radiotracer in bone depends on both local blood flow andosteoblastic activity, both of which may be pathologically modulated bythe tumor cells associated with the bone lesion. Resolving uptake maytherefore be attributable to either interruption of local blood flow,direct modulation of osteoblastic activity, a direct effect on the tumorcells in bone, or a combination of these processes. However, decreaseduptake on bone scan in men with CRPC has only been rarely noted withVEGF/VEGFR targeted therapy, despite numerous trials with such agents.Similarly, observations of decreased uptake on bone scan in CRPCpatients have only been reported rarely for abiraterone, which targetsthe cancer cells directly, and for dasatinib, which targets both cancercells and osteoclasts. Thus, targeting angiogenesis alone, orselectively targeting the tumor cells and/or osteoclasts, has notresulted in effects similar to those observed in the patients treatedwith Compound 1.

These results indicate a potential critical role for the MET and VEGFsignaling pathways in the progression of CRPC and point to the promisethat simultaneously targeting these pathways may hold in reducingmorbidity and mortality in this patient population.

Case Study 2

In a phase 2 adaptive randomized discontinuation trial (RDT), Compound 1resulted in resolution or stabilization of metastatic bone lesions onbone scan in 82 of 108 (76 percent) patients evaluable by this method.The majority of patients treated with Compound 1 reported reduced bonepain and reduced reliance upon narcotic pain medication. A total of 83patients had bone metastases and bone pain reported at baseline, and atleast one post-baseline assessment of pain status. Of these patients, 56(68%) had pain improvement at either Week 6 or 12. Narcotic analgesicmedication was required at baseline for control of bone pain in 67patients assessable for post-baseline review of narcotic consumption. Ofthese 67 patients, 47 (70%) were able to decrease or discontinuenarcotic medication for bone pain. Data on bone pain and narcotic use,as assessed by the investigator, were collected retrospectively. Theseresults suggest that Compound 1 can be used to treat and ameliorate boneand/or ameliorate bone metastases and pain due to other forms of cancer.

Patients with partial or complete resolution of metastatic bone lesionsby bone scan were more likely to remain free of disease progression atmonth 6, experience pain relief, reduce or eliminate their use ofnarcotic analgesics, achieve tumor regression, and experience markeddeclines in markers of bone turnover when compared to those who did notachieve bone scan resolution.

Updated progression-free survival (PFS) data show that Compound 1results in median PFS that appear to be similar in docetaxel-naïve andpretreated patients, and compare favorably to population matchedhistorical controls. In the randomized discontinuation phase of thisstudy, significant improvement in median PFS was observed in patientsrandomized to Compound 1. Despite only 31 patients randomized at week12, the results were highly statistically significant, suggestive of asizable treatment effect over placebo. Durable increases in hemoglobinlevels in anemic patients were also observed.

In the randomized discontinuation phase, a total of 31 patients with SDat week 12 were randomized to either placebo or Compound 1. From week 12onward, the investigator-assessed median PFS is 6 weeks (95% ConfidenceInterval [CI]: 5, 12 weeks) for the placebo group (n=17), and 21 weeks(95% CI: 11 weeks, upper limit not yet reached) for the Compound 1 group(n=14). The hazard ratio (HR) of 0.13 (95% CI 0.03, 0.50) stronglyfavored the Compound 1 arm and corresponded to an 87% reduction in therisk of progression for patients treated with Compound 1 compared withplacebo. These results were statistically significant (p=0.0007).

Excluding those randomized to placebo, the median PFS was 29 weeks forthe overall population (n=154). Median PFS in the subsets ofdocetaxel-naïve and -pretreated patients were 24 weeks (95% CI 24, upperlimit not yet reached) and 29 weeks (95% CI 18, 33), respectively. Thesedata indicate that Compound 1 treatment results in durable diseasecontrol in both docetaxel-naïve and pretreated populations.

Effects on bone scan were further assessed by an independent reviewer ina larger subset (n=108) of patients with bone metastases. Partial orcomplete resolution of bone scan was observed in 82 (76%) subjects.Twenty-three patients (21%) had stable disease (SD) on bone scan, andonly three patients (3%) had progressive disease in bone as their bestassessment.

Based on a post hoc analysis, patients with bone scan resolution (eithercomplete or partial) were more likely to be free of disease progressionat month 6 (61% vs. 35%), experience pain relief (83% vs. 43%), reduceor eliminate their need for narcotic analgesics (68% vs. 33%), achievetumor regression (78% vs. 58%), and experience marked declines inmarkers of bone turnover (60% vs. 43%), as compared to those who did notachieve bone scan resolution (stable or progressing bone scan).

Of 55 patients who had baseline bone pain, 42 had complete (n=10) orpartial (n=32) resolution and 13 had stabilization of disease by bonescan evaluation. Of these patients, 80%, 84%, and 38%, respectively,reported improvements in bone pain. These findings are the first to showan association between changes in bone scan imaging and improvement inclinical symptoms of disease.

Compound 1, an inhibitor of tumor growth, metastasis and angiogenesis,simultaneously targets MET and VEGFR2, key kinases involved in thedevelopment and progression of many cancers. Prominent expression of METhas been observed in primary and metastatic prostate carcinomas, withevidence for higher levels of expression in bone metastases.Overexpression of hepatocyte growth factor (HGF), the ligand for MET,has also been observed in prostate carcinoma, and increased plasmalevels of HGF are associated with decreased overall survival in CRPC.Data from preclinical studies also suggest that both HGF and MET areregulated by the androgen signaling pathway in prostate cancer, whereupregulation of MET signaling is associated with the transition toandrogen-independent tumor growth. Additionally, both the MET and VEGFRsignaling pathways also appear to play important roles in the functionof osteoblasts and osteoclasts—cells in the bone microenvironment thatare often dysregulated during the establishment and progression of bonemetastases.

The primary cause of morbidity and mortality in patients with CRPC ismetastasis to the bone, which occurs in about 90% of cases. Bonemetastases cause local disruption of normal bone remodeling, withlesions generally showing a propensity for an osteoblastic(bone-forming) phenotype on imaging. These lesions often lead toincreased skeletal fractures, spinal cord compression, and severe bonepain. Osteoblastic lesions are typically visualized in CRPC patients bybone scan, which detects rapid incorporation of 99 mTc-labeledmethylene-diphosphonate radiotracer into newly forming bone. Inaddition, increased blood levels of ALP and CTx, markers for osteoblastand osteoclast activity, respectively, are often observed in CRPCpatients with bone metastases, and are associated with shorter overallsurvival.

Case Study 4: Renal Cell Carcinoma with Bone Metastases

In a Phase I trial of patients with renal cell carcinoma with bonemetastases, tumor shrinkage was observed in a patient based bone scananalysis (FIG. 4). This patient showing resolution of bone lesions onbone scan also substantially reduced narcotic use by seven weeks tocontrol pain and continued on reduced narcotic use until week 25. Asecond patient with renal cell carcinoma with bone metastases and painat baseline (pain score 5 on a scale of 10) reported complete resolutionof pain by four weeks and remained pain-free as of week 73 of the study.

Case Study 5: Melanoma with Bone Metastases

In a randomized discontinuation study of 65 patients with melanoma withbone metastases, tumor shrinkage was observed in 39 of 65 patients (60percent) based bone scan analysis (FIG. 5).

Case Study 6: Breast Cancer with Bone Metastases

In a randomized discontinuation study of 44 patients with breast cancer,10 were found to be evaluable for bone scan resolution. Tumor shrinkagewas observed in 4 (forty percent) patients based bone scan analysis.

Case Study 7: Differentiated Thyroid Cancer with Bone Metastasis.

In a Phase 1 drug-drug trial, 15 patients with differentiated thyroidcancer were enrolled, one of whom had a bone metastasis to the skull.This lesion showed a dramatic response after 9 weeks of cabozantinibtreatment as judged by MRI (FIG. 6).

Study 8: Effect of Compound 1 Administration on CT^(x) PlasmaConcentration

The effects of Compound 1 treatment on osteoclast activity was alsoinvestigated based on the measurement of changes in plasma concentrationof Cross-linked C-terminal telopeptides of type-1 collagen (CT^(x))concentration in bisphosphonate treated and bisphosphonate naïvepatients with ovarian cancer that exhibited bone metastases (N=27).CT^(x) levels dropped in the majority of patients relative to baselinebased on plasma samples analyzed by ELISA at weeks 6 and 12 of thestudy. The results indicate the ability of Compound 1 to inhibit boneresorption.

Other Embodiments

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive.

The scope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the following appended claims, along with the fullscope of equivalents to which such claims are entitled.

1. A method for treating bone cancer associated with breast cancer,melanoma, renal cell carcinoma, sarcoma, lung cancer, or thyroid cancer,comprising administering to a patient in need of such treatment acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is halo; R²is halo; R³ is (C₁-C₆)alkyl; R⁴ is (C₁-C₆)alkyl; and Q is CH or N. 2.The method of claim 1, wherein the dual MET and VEGF modulator is acompound of Formula Ia

or a pharmaceutically acceptable salt thereof, wherein: R¹ is halo; R²is halo; and Q is CH or N.
 3. The method of claims 1-2, wherein thecompound of Formula I is compound I:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, which isN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.5. The method of claims 1-4, wherein the compound of Formula (I),Formula I(a) and Compound 1 is the (L)- or (D)-malate salt.
 6. Themethod of claims 1-5, wherein the compound of Formula (I) is in thecrystalline N-1 form of the (L) malate salt and/or the (D) malate salt.7. The method of claim 1, wherein the bone cancer is bone metastasesfrom lung cancer, breast cancer, melanoma, renal cell carcinoma, orthyroid cancer.
 8. A method for ameliorating abnormal deposition ofunstructured bone accompanied by increased skeletal fractures, spinalcord compression, and severe bone pain of bone metastases, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound of claims 2-6, optionally as apharmaceutical composition.
 9. A method for reducing or stabilizingmetastatic bone lesions associated with lung cancer, breast cancer,melanoma, renal cell carcinoma, or thyroid cancer, comprisingadministering a therapeutically effective amount of a compound claims2-6, optionally as a pharmaceutical composition, to a patient in need ofsuch treatment.
 10. A method for reducing, treating or minimizing bonepain due to metastatic bone lesions associated with lung cancer, breastcancer, melanoma, renal cell carcinoma, or thyroid cancer, comprisingadministering a therapeutically effective amount of a compound of claims2-6, optionally as a pharmaceutical composition, to a patient in need ofsuch treatment.
 11. A method for preventing bone metastases associatedwith lung cancer, breast cancer, melanoma, renal cell carcinoma, orthyroid cancer, comprising administering a therapeutically effectiveamount of a pharmaceutical formulation comprising claims 2-6, optionallyas a pharmaceutical composition, to a patient in need of such treatment.12. A method for extending the overall survival in patients with lungcancer, breast cancer, melanoma, renal cell carcinoma, or thyroid cancermetastasized to bone, comprising administering a therapeuticallyeffective amount of claims 2-6, optionally as a pharmaceuticalcomposition, to a patient in need of such treatment.
 13. A method fortreating bone cancer pain in an individual in need of such treatmentcomprising administering to the individual an effective amount of acompound of claims 2-6, optionally as a pharmaceutical composition. 14.The method of claim 13, wherein the bone cancer pain is from canceroriginated in bone.
 15. The method of claim 13, wherein the bone cancerpain is from osteosarcoma.
 16. The method of claim 13, wherein the bonecancer pain is from cancer metastasized to bone.
 17. The method of claim13, wherein the bone cancer pain is from breast cancer metastasized tobone.
 18. The method of claim 17, wherein the bone cancer pain is fromlung cancer metastasized to bone.
 19. The method of claim 13, whereinthe bone cancer pain is from sarcoma metastasized to bone.
 20. Themethod of claim 13, wherein the bone cancer pain is from renal cancermetastasized to bone.
 21. The method of claim 13, wherein the bonecancer pain is from thyroid cancer metastasized to bone.
 22. The methodof claim 13, wherein the bone cancer pain is from melanoma metastasizedto bone.